In the last 5 years, the landscape of HBV antiviral treatment has changed significantly to such an extent that most of the
clinical problems have been solved for countries where third-generation nucleo s(t)ide analogues (NUC), such as entecavir
(ETV) and tenofovir (TDF) are routinely available.1–3 Indeed, because of the high potency and high genetic barrier of these products, 5–6 years administration of ETV or TDF suppresses
viral replication in >95% of the cases, with increasing rates of HBeAg seroconversion (up to 50%) and HBsAg seroconversion
(up to 10%). In patients with long-lasting viral suppression, histological fibrosis is reverted, cirrhosis can regress and
clinical decompensation is fully prevented, whereas, hepatocellular carcinoma (HCC) remains the only complication leading
to anticipated liver-related death and liver transplantation.4–8 In patients with decompensated cirrhosis, administration of ETV and TDF improves survival, though the early mortality rates
and the development HCC despite effective viral suppression do represent major challenges for these delicate patients. Likewise,
the management of NUC-resistant (NUC-R) patients has also been revolutionised by the availability of TDF which efficiently
suppresses as monotherapy viral replication in most patients, independently of the resistant profile.9 Though efficacy must remain the major endpoint of any anti-HBV therapy, safety has also attracted much of attention in recent
years, given that antiviral treatment must be prolonged for several years, even decades, for most patients, as HBsAg clearance
remains the best stopping rule even in cirrhotics. Even in this regard, ETV and TDF have shown a good safety profile over
extended periods (up to 6 years) of treatment in registration and …